U.S. patent number 10,137,101 [Application Number 15/337,707] was granted by the patent office on 2018-11-27 for alkylamido compounds and uses thereof.
This patent grant is currently assigned to Nogra Pharma Limited. The grantee listed for this patent is Nogra Pharma Limited. Invention is credited to Sergio Baroni, Salvatore Bellinvia, Francesca Viti.
United States Patent |
10,137,101 |
Baroni , et al. |
November 27, 2018 |
Alkylamido compounds and uses thereof
Abstract
Disclosed herein are compounds that may be specific to PPAR
and/or EGF receptors, and methods of making and using same.
Inventors: |
Baroni; Sergio (Villa D'adda,
IT), Bellinvia; Salvatore (Mendrisio, CH),
Viti; Francesca (Salorino, CH) |
Applicant: |
Name |
City |
State |
Country |
Type |
Nogra Pharma Limited |
Dublin |
N/A |
IE |
|
|
Assignee: |
Nogra Pharma Limited (Dublin,
IE)
|
Family
ID: |
42562114 |
Appl.
No.: |
15/337,707 |
Filed: |
October 28, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
|
US 20170172956 A1 |
Jun 22, 2017 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14255255 |
Apr 17, 2014 |
9511041 |
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13201786 |
Jun 17, 2014 |
8754127 |
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PCT/EP2010/000935 |
Feb 16, 2010 |
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61287461 |
Dec 17, 2009 |
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61179062 |
May 18, 2009 |
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Foreign Application Priority Data
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Feb 16, 2009 [EP] |
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09425056 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61Q
19/08 (20130101); A61K 8/44 (20130101); C07D
319/08 (20130101); C07C 235/38 (20130101); A61Q
19/02 (20130101); A61Q 7/00 (20130101); A61Q
19/008 (20130101); A61K 31/196 (20130101); A61Q
5/00 (20130101); A61Q 19/06 (20130101); C07C
233/54 (20130101); A61P 17/10 (20180101); C07D
307/79 (20130101); A61K 8/42 (20130101); A61K
2800/78 (20130101) |
Current International
Class: |
A61K
31/196 (20060101); A61Q 7/00 (20060101); A61Q
5/00 (20060101); C07C 235/38 (20060101); C07D
319/08 (20060101); C07C 233/54 (20060101); C07D
307/79 (20060101); A61Q 19/08 (20060101); A61Q
19/06 (20060101); A61Q 19/02 (20060101); A61K
8/42 (20060101) |
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|
Primary Examiner: Pihonak; Sarah
Assistant Examiner: Deck; Jason
Attorney, Agent or Firm: Goodwin Procter LLP
Parent Case Text
This application is a continuation application of U.S. patent
application Ser. No. 14/255,255, filed on Apr. 17, 2014, which is a
continuation application of U.S. patent application Ser. No.
13/201,786, filed on Nov. 17, 2011, which is a U.S. national stage
application under 35 U.S.C. .sctn. 371 of International Application
No. PCT/EP2010/000935, filed on Feb. 16, 2010, which claims
priority to European Application No. 09425056.0, filed on Feb. 16,
2009, U.S. Patent Application No. 61/179,062, filed on May 18, 2009
and U.S. Patent Application No. 61/287,461, filed on Dec. 17, 2009,
each of which is incorporated by reference herein in its entirety.
Claims
What is claimed is:
1. A method of treating acne in a subject in need thereof, the
method comprising administering a therapeutically effective amount
of N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic acid, or a
pharmaceutically acceptable salt or a pharmaceutically acceptable
N-oxide thereof.
2. The method of claim 1, wherein the acne is at least one of: acne
vulgaris, comedo-type acne, polymorphic acne, acne rosacea,
nodulocystic acne, acne conglobata, senile acne, secondary acne,
solar acne, acne medicamentosa or occupational acne, or acne
hyperseborrhoea.
3. The method of claim 1, wherein
N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic acid, or a
pharmaceutically acceptable salt or a pharmaceutically acceptable
N-oxide thereof, is administered orally or topically.
4. A method of treating acne in a subject in need thereof, the
method comprising administering a pharmaceutical composition to the
subject, wherein the pharmaceutical composition comprises: a
therapeutically effective amount of
N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic acid, or a
pharmaceutically acceptable salt or a pharmaceutically acceptable
N-oxide thereof; and a pharmaceutically acceptable carrier.
5. The method of claim 4, wherein the acne is at least one of: acne
vulgaris, comedo-type acne, polymorphic acne, acne rosacea,
nodulocystic acne, acne conglobata, senile acne, secondary acne,
solar acne, acne medicamentosa or occupational acne, and acne
hyperseborrhoea.
6. The method of claim 4, wherein the pharmaceutical composition is
administered orally or topically.
Description
BACKGROUND
Peroxisome Proliferator Activated Receptors (PPARs) are members of
the nuclear hormone receptor super family, which are
ligand-activated transcription factors regulating gene expression.
Certain PPARs play roles in the regulation of cell differentiation,
development and metabolism of higher organisms.
Three types of PPAR has been identified: alpha, expressed in the
liver, kidney, heart and other tissues and organs, beta/delta
expressed for example in the brain, and gamma, expressed in three
forms: gamma1, gamma2, and gamma3. PPAR.gamma. receptors have been
associated with a number of disease states including dyslipidemia,
hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis,
hypertriglyceridemia, heart failure, myocardial infarction,
vascular diseases, cardiovascular diseases, hypertension, obesity,
inflammation, arthritis, cancer, Alzheimer's disease, skin
disorders, respiratory diseases, ophthalmic disorders, IBDs
(irritable bowel disease), ulcerative colitis and Crohn's
disease.
Further, treatment of tumor cells with ligands of PPAR.gamma.
receptors can induce a decrease in cellular proliferation, cell
differentiation and apoptosis, and therefore may be useful in
preventing carcinogenesis. Intestinal anti-inflammatory activity
may be dependent on binding and subsequent activation of
PPAR.gamma. receptors.
In addition, numerous studies have indicated that EGF receptor
inhibitors may control proliferation and spread of tumors.
Accordingly, molecules that modulate the activity of PPARs and/or
EGF receptors are useful as therapeutic agents in the treatment of
such diseases.
SUMMARY
This disclosure is generally directed to compounds which may be
specific to PPAR receptors and/or EGF receptors, and their use as,
for example, medicinal agents. Also provided are pharmaceutical
compositions comprising at least one disclosed compound, or
pharmaceutically acceptable salt or N-oxide thereof, and a
pharmaceutically acceptable carrier.
One embodiment provides compounds represented by formula I, and
compositions comprising such compounds:
##STR00001##
wherein X is C.sub.1-C.sub.3alkylene, optionally substituted with
one, two or three substituents selected from halogen or
hydroxyl;
R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl;
R.sub.2 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl;
R.sub.3 is independently selected, for each occurrence from the
group consisting of hydrogen, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkyl, cyano, C.sub.3-C.sub.6cycloalkyl, halogen,
hydroxyl, and nitro;
R.sub.4 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl;
R.sub.5 is hydrogen or C.sub.1-C.sub.6alkyl;
or pharmaceutically acceptable salts or N-oxides thereof.
Another embodiment provides compounds represented by formula II,
and compositions comprising such compounds:
##STR00002##
wherein R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl;
R.sub.2 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl;
R.sub.3 is independently selected, for each occurrence from the
group consisting of hydrogen, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkyl, cyano, C.sub.3-C.sub.6cycloalkyl, halogen,
hydroxyl, and nitro;
R.sub.5 is C.sub.1-C.sub.6alkyl;
or pharmaceutically acceptable salts or N-oxides thereof.
Also provided herein are methods of treating cancer (e.g.
colorectal cancer) such as tumors expressing PPAR receptors and/or
EGF receptors, comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of formula
I or II, or a pharmaceutically acceptable salt or N-oxides thereof.
Also contemplated herein are compositions that include a compound
represented by formula I or II and e.g., a pharmaceutically
acceptable excipient.
Also provided are compounds represented by formulas I and II for
use in therapy and/or for the manufacture of a medicament for the
treatment of cancer such as colorectal cancer.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 depicts the % mortality of mice receiving TNBS
(trinitrobenzene sulfonic acid) versus mice receiving TNBS and
N-acetyl E2 in a murine colitis model.
FIG. 2 depicts the observed level of colonic lesions in mice
receiving TNBS versus mice receiving TNBS and N-acetyl E2 in a
murine colitis model.
FIG. 3 depicts the observed level of MPO activity in mice receiving
TNBS versus mice receiving TNBS and N-acetyl E2 in a murine colitis
model.
FIG. 4 depicts the observed level of colonic inflammation in mice
receiving TNBS versus mice receiving TNBS and N-acetyl E2 in a
murine colitis model.
FIG. 5 depicts effects of a disclosed compound on human
keratinocytes.
FIG. 6 depicts inhibition of TNF alpha by H.sub.2O.sub.2 and a
disclosed compound.
FIG. 7 depicts inhibition on mRNA expression of IL-6 induced by the
presence of IFN-gamma.
FIG. 8 depicts inhibition of a disclosed compound on the activation
of NF-kB.
FIG. 9 depicts inhibition of a disclosed compound on protein
expression of IL-6 induced by presence of LPS.
FIG. 10 depicts effect of a disclosed compound on human
sebocytes.
FIG. 11 depicts inhibitory capacity of a disclosed compound on
sebogenesis induced by lipid type stimulus.
FIG. 12A and FIG. 12B depict the results of a fatty acid assay and
squalene analysis of sebogenesis inhibition, respectively.
FIG. 13 depicts treatment with linoleic acid and testosterone with
lipidogenic stimulus.
DETAILED DESCRIPTION
The features and other details of the disclosure will now be more
particularly described. Before further description of the present
invention, certain terms employed in the specification, examples
and appended claims are collected here. These definitions should be
read in light of the remainder of the disclosure and understood as
by a person of skill in the art. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
commonly understood by a person of ordinary skill in the art.
Definitions
"Treating" includes any effect, e.g., lessening, reducing,
modulating, or eliminating, that results in the improvement of the
condition, disease, disorder and the like.
The term "alkenyl" as used herein refers to an unsaturated straight
or branched hydrocarbon having at least one carbon-carbon double
bond, such as a straight or branched group of 2-12, 2-10, or 2-6
carbon atoms, referred to herein as C.sub.2-C.sub.12alkenyl,
C.sub.2-C.sub.10alkenyl, and C.sub.2-C.sub.6alkenyl, respectively.
Exemplary alkenyl groups include, but are not limited to, vinyl,
allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,
hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,
4-(2-methyl-3-butene)-pentenyl, etc.
The term "alkoxy" as used herein refers to an alkyl group attached
to an oxygen (--O-alkyl-). Exemplary alkoxy groups include, but are
not limited to, groups with an alkyl, alkenyl or alkynyl group of
1-12, 1-8, or 1-6 carbon atoms, referred to herein as
C.sub.1-C.sub.12alkoxy, C.sub.1-C.sub.8alkoxy, and
C.sub.1-C.sub.6alkoxy, respectively. Exemplary alkoxy groups
include, but are not limited to methoxy, ethoxy, etc. Similarly,
exemplary "alkenoxy" groups include, but are not limited to
vinyloxy, allyloxy, butenoxy, etc.
The term "alkyl" as used herein refers to a saturated straight or
branched hydrocarbon, such as a straight or branched group of 1-12,
1-10, or 1-6 carbon atoms, referred to herein as
C.sub.1-C.sub.12alkyl, C.sub.1-C.sub.10alkyl, and
C.sub.1-C.sub.6alkyl, respectively. Exemplary alkyl groups include,
but are not limited to, methyl, ethyl, propyl, isopropyl,
2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,
3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,
2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,
2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,
2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,
isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,
octyl, etc. In certain embodiments, alkyl refers to C.sub.1-C.sub.6
alkyl. In certain embodiments, cycloalkyl refers to
C.sub.3-C.sub.6cycloalkyl.
Alkyl, alkenyl and alkynyl groups can, in some embodiments, be
optionally be substituted with or interrupted by at least one group
selected from alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido,
amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate,
carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,
haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone,
nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide,
sulfonamido, sulfonyl and thiocarbonyl.
The term "alkynyl" as used herein refers to an unsaturated straight
or branched hydrocarbon having at least one carbon-carbon triple
bond, such as a straight or branched group of 2-12, 2-8, or 2-6
carbon atoms, referred to herein as C.sub.2-C.sub.12alkynyl,
C.sub.2-C.sub.8alkynyl, and C.sub.2-C.sub.6alkynyl, respectively.
Exemplary alkynyl groups include, but are not limited to, ethynyl,
propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl,
etc.
The term "amide" or "amido" as used herein refers to a radical of
the form --R.sub.aC(O)N(R.sub.b)--,
--R.sub.aC(O)N(R.sub.b)R.sub.c--, or --C(O)NR.sub.bR.sub.c, wherein
R.sub.a, R.sub.b and R.sub.c are each independently selected from
alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,
carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl,
heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, and nitro.
The amide can be attached to another group through the carbon, the
nitrogen, R.sub.b, R.sub.c, or R.sub.a. The amide also may be
cyclic, for example R.sub.b and R.sub.c, R.sub.a and R.sub.b, or
R.sub.a and R.sub.c may be joined to form a 3- to 12-membered ring,
such as a 3- to 10-membered ring or a 5- to 6-membered ring. The
term "carboxamido" refers to the structure
--C(O)NR.sub.bR.sub.c.
The term "amidino" as used herein refers to a radical of the form
--C(.dbd.NR)NR'R'' where R, R', and R'' can each independently be
selected from alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl,
cyano, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,
ketone and nitro.
The term "amine" or "amino" as used herein refers to a radical of
the form --NR.sub.dR.sub.e, --N(R.sub.d)R.sub.e--, or
--R.sub.eN(R.sub.d)R.sub.f-- where R.sub.d, R.sub.e, and R.sub.f
are independently selected from alkoxy, alkyl, alkenyl, alkynyl,
amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether,
formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,
hydroxyl, ketone, and nitro. The amino can be attached to the
parent molecular group through the nitrogen, R.sub.d, R.sub.e or
R.sub.f. The amino also may be cyclic, for example any two of Rd,
Re or Rf may be joined together or with the N to form a 3- to
12-membered ring, e.g., morpholino or piperidinyl. The term amino
also includes the corresponding quaternary ammonium salt of any
amino group, e.g., --[N(Rd)(Re)(Rf)]+. Exemplary amino groups
include aminoalkyl groups, wherein at least one of R.sub.d,
R.sub.e, or R.sub.f is an alkyl group.
The term "aryl" as used herein refers to refers to a mono-, bi-, or
other multi-carbocyclic, aromatic ring system. In certain
embodiments, aryl refers to a monocyclic and/or bicyclic, 5 to 6
membered ring. The aromatic ring may be substituted at one or more
ring positions with substituents selected from alkanoyl, alkoxy,
alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl,
azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester,
ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,
hydroxyl, imino, ketone, nitro, phosphate, phosphonato,
phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and
thiocarbonyl. The term "aryl" also includes polycyclic ring systems
having two or more cyclic rings in which two or more carbons are
common to two adjoining rings (the rings are "fused rings") wherein
at least one of the rings is aromatic, e.g., the other cyclic rings
may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
Exemplary aryl groups include, but are not limited to, phenyl,
tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as
well as benzo-fused carbocyclic moieties such as
5,6,7,8-tetrahydronaphthyl.
The term "arylalkyl" as used herein refers to an aryl group having
at least one alkyl substituent, e.g. -aryl-alkyl-. Exemplary
arylalkyl groups include, but are not limited to, arylalkyls having
a monocyclic aromatic ring system, wherein the ring comprises 6
carbon atoms. For example, "phenylalkyl" includes
phenylC.sub.4alkyl, benzyl, 1-phenylethyl, 2-phenylethyl, etc.
The term "carbonyl" as used herein refers to the radical
--C(O)--.
The term "carboxamido" as used herein refers to the radical
--C(O)NRR', where R and R' may be the same or different. R and R'
may be selected from, for example, alkyl, aryl, arylalkyl,
cycloalkyl, formyl, haloalkyl, heteroaryl and heterocyclyl.
The term "carboxy" as used herein refers to the radical --COOH or
its corresponding salts, e.g. --COONa, etc.
The term "cyano" as used herein refers to the radical --CN.
The term "cycloalkoxy" as used herein refers to a cycloalkyl group
attached to an oxygen.
The term "cycloalkyl" as used herein refers to a monovalent
saturated or unsaturated cyclic, bicyclic, or bridged bicyclic
hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to
herein, e.g., as "C.sub.4-8cycloalkyl," derived from a cycloalkane.
Exemplary cycloalkyl groups include, but are not limited to,
cyclohexanes, cyclohexenes, cyclopentanes, cyclopentenes,
cyclobutanes and cyclopropanes. Cycloalkyl groups may be
substituted with alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido,
amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate,
carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,
haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone,
nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide,
sulfonamido, sulfonyl and thiocarbonyl. Cycloalkyl groups can be
fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain
embodiments, cycloalkyl refers to C.sub.3-C.sub.6 alkyl.
The terms "halo" or "halogen" or "Hal" as used herein refer to F,
Cl, Br, or I.
The term "haloalkyl" as used herein refers to an alkyl group
substituted with one or more halogen atoms.
The term "nitro" as used herein refers to the radical
--NO.sub.2.
The term "phenyl" as used herein refers to a 6-membered carbocyclic
aromatic ring. The phenyl group can also be fused to a cyclohexane
or cyclopentane ring. Phenyl can be substituted with one or more
substituents including alkanoyl, alkoxy, alkyl, alkenyl, alkynyl,
amido, amidino, amino, aryl, arylalkyl, azido, carbamate,
carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl,
halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino,
ketone, nitro, phosphate, phosphonato, phosphinato, sulfate,
sulfide, sulfonamido, sulfonyl and thiocarbonyl.
The term "phosphate" as used herein refers to the radical
--OP(O)(OR.sub.aa).sub.2 or its anions. The term "phosphanate"
refers to the radical --P(O)(OR.sub.aa).sub.2 or its anions. The
term "phosphinate" refers to the radical --PR.sub.aa(O)(OR.sub.aa)
or its anion, where each R.sub.aa can be selected from, for
example, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
hydrogen, haloalkyl, heteroaryl, and heterocyclyl.
The term "pharmaceutically acceptable carrier" or "pharmaceutically
acceptable excipient" as used herein refers to any and all
solvents, dispersion media, coatings, isotonic and absorption
delaying agents, and the like, that are compatible with
pharmaceutical administration. The use of such media and agents for
pharmaceutically active substances is well known in the art. The
compositions may also contain other active compounds providing
supplemental, additional, or enhanced therapeutic functions.
The term "pharmaceutical composition" as used herein refers to a
composition comprising at least one compound as disclosed herein
formulated together with one or more pharmaceutically acceptable
carriers.
"Individual," "patient," or "subject" are used interchangeably and
include to any animal, including mammals, preferably mice, rats,
other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,
or primates, and most preferably humans. The compounds of the
invention can be administered to a mammal, such as a human, but can
also be other mammals such as an animal in need of veterinary
treatment, e.g., domestic animals (e.g., dogs, cats, and the like),
farm animals (e.g., cows, sheep, pigs, horses, and the like) and
laboratory animals (e.g., rats, mice, guinea pigs, and the like).
The mammal treated in the methods of the invention is desirably a
mammal in whom modulation of PPAR and/or EGF receptors is desired.
"Modulation" includes antagonism (e.g., inhibition), agonism,
partial antagonism and/or partial agonism.
In the present specification, the term "therapeutically effective
amount" means the amount of the subject compound that will elicit
the biological or medical response of a tissue, system, animal or
human that is being sought by the researcher, veterinarian, medical
doctor or other clinician. The compounds of the invention are
administered in therapeutically effective amounts to treat a
disease. Alternatively, a therapeutically effective amount of a
compound is the quantity required to achieve a desired therapeutic
and/or prophylactic effect, such as an amount which results in the
prevention of or a decrease in the symptoms associated with a
disease associated with PPAR and/or EGF receptors.
The term "pharmaceutically acceptable salt(s)" as used herein
refers to salts of acidic or basic groups that may be present in
compounds used in the present compositions. Compounds included in
the present compositions that are basic in nature are capable of
forming a wide variety of salts with various inorganic and organic
acids. The acids that may be used to prepare pharmaceutically
acceptable acid addition salts of such basic compounds are those
that form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions, including but not limited to
malate, oxalate, chloride, bromide, iodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds
included in the present compositions that include an amino moiety
may form pharmaceutically acceptable salts with various amino
acids, in addition to the acids mentioned above. Compounds included
in the present compositions that are acidic in nature are capable
of forming base salts with various pharmacologically acceptable
cations. Examples of such salts include alkali metal or alkaline
earth metal salts and, particularly, calcium, magnesium, sodium,
lithium, zinc, potassium, and iron salts.
The compounds of the disclosure may contain one or more chiral
centers and/or double bonds and, therefore, exist as stereoisomers,
such as geometric isomers, enantiomers or diastereomers. The term
"stereoisomers" when used herein consist of all geometric isomers,
enantiomers or diastereomers. These compounds may be designated by
the symbols "R" or "S," depending on the configuration of
substituents around the stereogenic carbon atom. The present
invention encompasses various stereoisomers of these compounds and
mixtures thereof. Stereoisomers include enantiomers and
diastereomers. Mixtures of enantiomers or diastereomers may be
designated "(.+-.)" in nomenclature, but the skilled artisan will
recognize that a structure may denote a chiral center
implicitly.
Individual stereoisomers of compounds of the present invention can
be prepared synthetically from commercially available starting
materials that contain asymmetric or stereogenic centers, or by
preparation of racemic mixtures followed by resolution methods well
known to those of ordinary skill in the art. These methods of
resolution are exemplified by (1) attachment of a mixture of
enantiomers to a chiral auxiliary, separation of the resulting
mixture of diastereomers by recrystallization or chromatography and
liberation of the optically pure product from the auxiliary, (2)
salt formation employing an optically active resolving agent, or
(3) direct separation of the mixture of optical enantiomers on
chiral chromatographic columns. Stereoisomeric mixtures can also be
resolved into their component stereoisomers by well known methods,
such as chiral-phase gas chromatography, chiral-phase high
performance liquid chromatography, crystallizing the compound as a
chiral salt complex, or crystallizing the compound in a chiral
solvent. Stereoisomers can also be obtained from
stereomerically-pure intermediates, reagents, and catalysts by well
known asymmetric synthetic methods.
Geometric isomers can also exist in the compounds of the present
invention. The symbol denotes a bond that may be a single, double
or triple bond as described herein. The present invention
encompasses the various geometric isomers and mixtures thereof
resulting from the arrangement of substituents around a
carbon-carbon double bond or arrangement of substituents around a
carbocyclic ring. Substituents around a carbon-carbon double bond
are designated as being in the "Z" or "E" configuration wherein the
terms "Z" and "E" are used in accordance with IUPAC standards.
Unless otherwise specified, structures depicting double bonds
encompass both the "E" and "Z" isomers.
Substituents around a carbon-carbon double bond alternatively can
be referred to as "cis" or "trans," where "cis" represents
substituents on the same side of the double bond and "trans"
represents substituents on opposite sides of the double bond. The
arrangement of substituents around a carbocyclic ring are
designated as "cis" or "trans." The term "cis" represents
substituents on the same side of the plane of the ring and the term
"trans" represents substituents on opposite sides of the plane of
the ring. Mixtures of compounds wherein the substituents are
disposed on both the same and opposite sides of plane of the ring
are designated "cis/trans."
The compounds disclosed herein can exist in solvated as well as
unsolvated forms with pharmaceutically acceptable solvents such as
water, ethanol, and the like, and it is intended that the invention
embrace both solvated and unsolvated forms. In one embodiment, the
compound is amorphous. In one embodiment, the compound is a
polymorph. In another embodiment, the compound is in a crystalline
form.
The invention also embraces isotopically labeled compounds of the
invention which are identical to those recited herein, except that
one or more atoms are replaced by an atom having an atomic mass or
mass number different from the atomic mass or mass number usually
found in nature. Examples of isotopes that can be incorporated into
compounds of the invention include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, fluorine and chlorine, such as
.sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl,
respectively.
Certain isotopically-labeled disclosed compounds (e.g., those
labeled with .sup.3H and .sup.14C) are useful in compound and/or
substrate tissue distribution assays. Tritiated (i.e., .sup.3H) and
carbon-14 (i.e., .sup.14C) isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium (i.e., .sup.2H) may afford
certain therapeutic advantages resulting from greater metabolic
stability (e.g., increased in vivo half-life or reduced dosage
requirements) and hence may be preferred in some circumstances.
Isotopically labeled compounds of the invention can generally be
prepared by following procedures analogous to those disclosed in
the e.g., Examples herein by substituting an isotopically labeled
reagent for a non-isotopically labeled reagent.
The term "prodrug" refers to compounds that are transformed in vivo
to yield a disclosed compound or a pharmaceutically acceptable
salt, hydrate or solvate of the compound. The transformation may
occur by various mechanisms, such as through hydrolysis in blood.
For example, if a compound of the invention or a pharmaceutically
acceptable salt, hydrate or solvate of the compound contains a
carboxylic acid functional group, a prodrug can comprise an ester
formed by the replacement of the hydrogen atom of the acid group
with a group such as (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
Similarly, if a compound of the invention contains an alcohol
functional group, a prodrug can be formed by the replacement of the
hydrogen atom of the alcohol group with a group such as
(C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
If a compound of the invention incorporates an amine functional
group, a prodrug can be formed by the replacement of a hydrogen
atom in the amine group with a group such as R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7)cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl-natural .alpha.-aminoacyl, --C(OH)C(O)OY.sup.1
wherein Y.sup.1 is H, (C.sub.1-C.sub.6)alkyl or benzyl,
--C(OY.sup.2)Y.sup.3 wherein Y.sup.2 is (C.sub.1-C.sub.4) alkyl and
Y.sup.3 is (C.sub.1-C.sub.6)alkyl, carboxy(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sup.4)Y.sup.5
wherein Y.sup.4 is H or methyl and Y.sup.5 is mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino, morpholino, piperidin-1-yl or
pyrrolidin-1-yl.
The disclosure provides, at least in part, compounds represented by
formula I, as depicted below. Also contemplated herein are
compositions that include a compound represented by formula I and
e.g., a pharmaceutically acceptable carrier.
##STR00003##
wherein X is C.sub.1-C.sub.3alkylene, optionally substituted with
one, two or three substituents selected from halogen or
hydroxyl;
R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl;
R.sub.2 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl;
R.sub.3 is independently selected, for each occurrence from the
group consisting of hydrogen, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkyl, cyano, C.sub.3-C.sub.6cycloalkyl, halogen,
hydroxyl, and nitro;
R.sub.4 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl;
R.sub.5 is C.sub.1-C.sub.6alkyl;
or pharmaceutically acceptable salts or N-oxides thereof.
In one embodiment, R.sub.1 can be C.sub.1-C.sub.6alkyl, such as
methyl. In one embodiment, R.sub.2 can be hydrogen. In another
embodiment, R.sub.3 can be selected from the group consisting of
hydrogen, C.sub.1-C.sub.6alkyl, halogen, and hydroxyl. In a further
embodiment, R.sub.3 can be hydrogen. In one embodiment, R.sub.4 and
R.sub.5 can each be C.sub.1-C.sub.6alkyl. In another embodiment,
R.sub.4 may be hydrogen and R.sub.5 may be methyl. In one
embodiment, X may be (CH.sub.2).sub.n, wherein n is 1 or 2, such as
1.
In another embodiment, --NR.sub.2--COR.sub.1 can be in the meta
position relative to X as shown in formula III.
##STR00004##
In another embodiment, --NR.sub.2--COR.sub.1 can be in the para
position relative to X as shown in formula IV.
##STR00005##
The disclosure provides, at least in part, compounds represented by
formula II, as depicted below. Also contemplated herein are
compositions that include a compound represented by formula II and
e.g., a pharmaceutically acceptable carrier.
##STR00006##
wherein R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl;
R.sub.2 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl;
R.sub.3 is independently selected, for each occurrence from the
group consisting of hydrogen, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkyl, cyano, C.sub.3-C.sub.6cycloalkyl, halogen,
hydroxyl, and nitro;
R.sub.5 is hydrogen or C.sub.1-C.sub.6alkyl;
or pharmaceutically acceptable salts or N-oxides thereof.
Compounds of Formula V are also contemplated as shown below, as
well as compositions that include a compound represented by formula
V and e.g., a pharmaceutically acceptable carrier.
##STR00007##
wherein R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl;
R.sub.3 is independently selected, for each occurrence from the
group consisting of hydrogen, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6alkyl, cyano, C.sub.3-C.sub.6cycloalkyl, halogen,
hydroxyl, and nitro;
R.sub.4 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6alkyl;
R.sub.5 is hydrogen or C.sub.1-C.sub.6alkyl; and
A is a fused five or six membered heterocycle;
or pharmaceutically acceptable salts or N-oxides thereof.
In one embodiment, R.sub.1 can be C.sub.1-C.sub.6alkyl, such as
methyl. In another embodiment, R.sub.1 and R.sub.3 can each be
C.sub.1-C.sub.6alkyl, such as methyl. In one embodiment, R.sub.2
can be hydrogen.
In some embodiments, a compound can be represented by
##STR00008##
wherein p is 1 or 2;
R.sub.1 is selected from the group consisting of
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, and C.sub.2-C.sub.6alkynyl;
R.sub.4 and R.sub.8 are each independently selected from the group
consisting of hydrogen and C.sub.1-C.sub.6alkyl;
or pharmaceutically acceptable salts or N-oxides thereof.
Contemplated compounds, and pharmaceutical compositions, comprising
at least one compound, may be selected from the group consisting
of: N-acetyl-(R)-3-(4-aminophenyl)-2-methoxypropionic acid
(Compound A), N-acetyl-(S)-3-(4-aminophenyl)-2-methoxypropionic
acid (Compound B), racemic
N-acetyl-3-(4-aminophenyl)-2-methoxypropionic acid (compound
AB);
##STR00009## ##STR00010## 4-acetamino-N-hydroxy-2-methoxybenzamide;
1-acetyl-6-methoxy-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
5-acetamido-2hydroxybenzoic acid (e.g., acetalyated
5-aminosalicyclic acid) or pharmaceutically acceptable salts or
N-oxides thereof.
The present disclosure also provides pharmaceutical compositions
comprising compounds as disclosed herein formulated together with
one or more pharmaceutically acceptable carriers. These
formulations include those suitable for oral, rectal, topical,
buccal and parenteral (e.g., subcutaneous, intramuscular,
intradermal, or intravenous) administration, although the most
suitable form of administration in any given case will depend on
the degree and severity of the condition being treated and on the
nature of the particular compound being used.
Therapeutic Applications
The disclosure further provides, in some embodiments, methods of
modulating activity of one or more PPAR and/or EGF receptors
comprising exposing said receptor to a compound of the invention.
For example, provided herein are methods of treating a disease
associated with expression or activity of one or more PPAR and/or
EGF receptors in a patient comprising administering to the patient
a therapeutically effective amount of a compound of the
invention.
One embodiment of the invention provides a method of treating
tumors of the esophagus, stomach, pancreas, colon, prostate,
breast, uterus, kidneys, and lungs comprising administering to a
subject in need thereof a therapeutically effective amount of a
compound of the invention. Also contemplated herein is a method for
delaying clinical manifestation of a colorectal tumor, or a solid
tumor (e.g., a breast, prostate, lung or hepatocellular carcinoma)
in a patient, for example, a patient at risk of colorectal cancer,
comprising administering to the patient an effective amount of a
compound disclosed herein. Administering such a compound may be on
e.g., at least a daily basis. For example, the delay of clinical
manifestation of a colorectal tumor in a patient as a consequence
of administering a compound disclosed here may be at least e.g., 6
months, 1 year, 18 months or even 2 years or more as compared to a
patient who is not administered a compound such as one disclosed
herein.
Another embodiment of the invention provides a method of treating
or ameliorating chronic inflammation, such as Crohn's disease or
ulcerative colitis, comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of the
invention.
Methods of treating dermatological conditions are also provided,
such as the treatment of at least one of: acne vulgaris,
comedo-type acne, polymorphic acne, acne rosacea, nodulocystic
acne, acne conglobata, senile acne, secondary acne, solar acne,
acne medicamentosa or occupational acne, ichthyosis, Darrier's
disease, keratosis palmaris or plantaris, cutaneous, mucosal or
ungual psoriasis, skin disorders due to exposure to UV radiation,
of skin aging, photoinduced or chronological or actinic
pigmentations and keratoses, acne hyperseborrhoea, simple
seborrhoea or seborrhoeic dermatitis, cicatrization disorders or
stretch marks. Methods of treating atopic dermatitis is also
contemplated. The composition may be administered orally or
topically.
For example, continuous sebum production can increase in acne
patients; and application of a sebum inhibitor, such as disclosed
herein, may be useful in the treatment of acne, seborrhea or
alopecia. In another example, chronic inflammation of hair
follicles (keratinocytes) can be an indication of e.g., androgenic
alopecia. An inhibitor of such inflammation such as disclosed
herein can be useful in e.g., the treatment of hair loss.
Provided herein are methods of treating fine lines, wrinkles or
surface irregularities of the skin, or protecting from and/or
ameliorating free radical damage to the skin, comprising topically
administering an effective amount of a composition comprising a
compound of the invention.
In some embodiments, a method of treating hair loss in a patient
suffering from unwanted hair loss is provided, comprising
administering an effective amount of a composition comprising a
disclosed compound. Methods of treating alopecia areata,
androgenetic alopecia and/or telogenic defluvium are
contemplated.
Also provided herein are methods of treating an age-related
disorder selected from the group consisting of: diabetes,
cataracts, Alzheimer's disease, Parkinson's disease, macular
degeneration, retinal ulcers or retinal vasculitis, comprising
administering an effective amount of a composition comprising a
disclosed compound. Also provided herein are methods of treating a
vascular or cardiac disorder, comprising identifying a patient
suffering from or at risk of developing said disorder and
administering to said patient an effective amount of a disclosed
compound as defined above. For example, a cardiac disorder being
treated may be chosen from chronic coronary ischemia,
arteriosclerosis, congestive heart failure, ischemic or reperfusion
related injury, angina, atherosclerosis, myocardial infarction,
stroke and myocardial hypertrophy. In another embodiment, a method
of treating an autoimmune disorder is provided, wherein the
autoimmune disorder may be chosen from, for example, Addison's
disease, chronic thyroiditis, dermatomyositis, Grave's disease,
multiple sclerosis, systemic lupus erythematosis, psoriasis, or
rheumatoid arthritis. (Intra-articular administration of disclosed
compounds and/or compositions is contemplated herein, in some
embodiments, for e.g., arthritis or any other contemplated
indication). Other contemplated indications include mucosal
disorders such as aphtae (mouth ulcers) and/or gingivitis. In
another embodiment, treatment of ocular disorders is also
contemplated such as diabetic retinopathy or age-related macular
degeneration.
The compounds of the invention may be administered to patients
(animals and humans) in need of such treatment in dosages that will
provide optimal pharmaceutical efficacy. It will be appreciated
that the dose required for use in any particular application will
vary from patient to patient, not only with the particular compound
or composition selected, but also with the route of administration,
the nature of the condition being treated, the age and condition of
the patient, concurrent medication or special diets then being
followed by the patient, and other factors which those skilled in
the art will recognize, with the appropriate dosage ultimately
being at the discretion of the attendant physician. For treating
clinical conditions and diseases noted above, the compound of this
invention may be administered orally, topically, parenterally, by
inhalation spray or rectally in dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intrasternal
injection or infusion techniques.
Generally, a therapeutically effective amount of active component
will be in the range of from about 0.1 mg/kg to about 100 mg/kg,
optionally from about 1 mg/kg to about 100 mg/kg, optionally from
about 1 mg/kg to 10 mg/kg. The amount administered will depend on
variables such as the type and extent of disease or indication to
be treated, the overall health status of the particular patient,
the relative biological efficacy of the compounds, formulation of
compounds, the presence and types of excipients in the formulation,
and the route of administration. The initial dosage administered
may be increased beyond the upper level in order to rapidly achieve
the desired blood-level or tissue level, or the initial dosage may
be smaller than the optimum and the daily dosage may be
progressively increased during the course of treatment depending on
the particular situation. Human dosage can be optimized, e.g., in a
conventional Phase I dose escalation study designed to run from 0.5
mg/kg to 20 mg/kg. Dosing frequency can vary, depending on factors
such as route of administration, dosage amount and the disease
condition being treated. Exemplary dosing frequencies are once per
day, once per week and once every two weeks.
Contemplated formulations or compositions comprise a disclosed
compound and typically include a compound a pharmaceutically
acceptable carrier.
Contemplated compositions may be administered by various means,
depending on their intended use, as is well known in the art. For
example, if compositions of the present invention are to be
administered orally, they may be formulated as tablets, capsules,
granules, powders or syrups. Alternatively, formulations of the
present invention may be administered parenterally as injections
(intravenous, intramuscular or subcutaneous), drop infusion
preparations or enemas or suppositories. For application by the
ophthalmic mucous membrane route, compositions of the present
invention may be formulated as eyedrops or eye ointments. These
formulations may be prepared by conventional means, and, if
desired, the compositions may be mixed with any conventional
additive, such as an excipient, a binder, a disintegrating agent, a
lubricant, a corrigent, a solubilizing agent, a suspension aid, an
emulsifying agent or a coating agent.
In formulations of the subject invention, wetting agents,
emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents,
coating agents, sweetening, flavoring and perfuming agents,
preservatives and antioxidants may be present in the formulated
agents.
Subject compositions may be suitable for oral, nasal, topical
(including buccal and sublingual), rectal, vaginal, aerosol and/or
parenteral administration. The formulations may conveniently be
presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. The amount of composition that
may be combined with a carrier material to produce a single dose
vary depending upon the subject being treated, and the particular
mode of administration.
Methods of preparing these formulations include the step of
bringing into association compositions of the present invention
with the carrier and, optionally, one or more accessory
ingredients. In general, the formulations are prepared by uniformly
and intimately bringing into association agents with liquid
carriers, or finely divided solid carriers, or both, and then, if
necessary, shaping the product.
Formulations suitable for oral administration may be in the form of
capsules, cachets, pills, tablets, lozenges (using a flavored
basis, usually sucrose and acacia or tragacanth), powders,
granules, or as a solution or a suspension in an aqueous or
non-aqueous liquid, or as an oil-in-water or water-in-oil liquid
emulsion, or as an elixir or syrup, or as pastilles (using an inert
base, such as gelatin and glycerin, or sucrose and acacia), each
containing a predetermined amount of a subject composition thereof
as an active ingredient. Compositions of the present invention may
also be administered as a bolus, electuary, or paste.
In solid dosage forms for oral administration (capsules, tablets,
pills, film-coated tablets, sugar-coated tablets, powders, granules
and the like), the subject composition is mixed with one or more
pharmaceutically acceptable carriers, such as sodium citrate or
dicalcium phosphate, and/or any of the following: (1) fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; (3) humectants, such as glycerol; (4)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, and sodium
carbonate; (5) solution retarding agents, such as paraffin; (6)
absorption accelerators, such as quaternary ammonium compounds; (7)
wetting agents, such as, for example, acetyl alcohol and glycerol
monostearate; (8) absorbents, such as kaolin and bentonite clay;
(9) lubricants, such a talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof; and (10) coloring agents. In the case of capsules, tablets
and pills, the compositions may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugars, as well as high molecular
weight polyethylene glycols and the like.
Formulations and compositions may include micronized crystals of
the disclosed compounds. Micronization may be performed on crystals
of the compounds alone, or on a mixture of crystals and a part or
whole of pharmaceutical excipients or carriers. Mean particle size
of micronized crystals of a disclosed compound may be for example
about 5 to about 200 microns, or about 10 to about 110 microns.
A tablet may be made by compression or molding, optionally with one
or more accessory ingredients. Compressed tablets may be prepared
using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the subject composition moistened with an inert liquid
diluent. Tablets, and other solid dosage forms, such as film coated
tablets or sugar coated tablets, capsules, pills and granules, may
optionally be scored or prepared with coatings and shells, such as
enteric coatings and other coatings well known in the
pharmaceutical-formulating art.
Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the subject
composition, the liquid dosage forms may contain inert diluents
commonly used in the art, such as, for example, water or other
solvents, solubilizing agents and emulsifiers, such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
oils (in particular, cottonseed, groundnut, corn, germ, olive,
castor and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan,
cyclodextrins and mixtures thereof.
Suspensions, in addition to the subject composition, may contain
suspending agents as, for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, and mixtures thereof.
Formulations for rectal or vaginal administration may be presented
as a suppository, which may be prepared by mixing a subject
composition with one or more suitable non-irritating excipients or
carriers comprising, for example, cocoa butter, polyethylene
glycol, a suppository wax or a salicylate, and which is solid at
room temperature, but liquid at body temperature and, therefore,
will melt in the body cavity and release the active agent.
Formulations which are suitable for vaginal administration also
include pessaries, tampons, creams, gels, pastes, foams or spray
formulations containing such carriers as are known in the art to be
appropriate.
Dosage forms for transdermal or topical administration of a subject
composition include powders, sprays, ointments, pastes, creams,
lotions, gels, solutions, patches and inhalants. The active
component may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to
a subject composition, excipients, such as animal and vegetable
fats, oils, waxes, paraffins, starch, tragacanth, cellulose
derivatives, polyethylene glycols, silicones, bentonites, silicic
acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays may contain, in addition to a subject
composition, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays may additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
Compositions and compounds of the present invention may
alternatively be administered by aerosol. This is accomplished by
preparing an aqueous aerosol, liposomal preparation or solid
particles containing the compound. A non-aqueous (e.g.,
fluorocarbon propellant) suspension could be used. Sonic nebulizers
may be used because they minimize exposing the agent to shear,
which may result in degradation of the compounds contained in the
subject compositions.
Ordinarily, an aqueous aerosol is made by formulating an aqueous
solution or suspension of a subject composition together with
conventional pharmaceutically acceptable carriers and stabilizers.
The carriers and stabilizers vary with the requirements of the
particular subject composition, but typically include non-ionic
surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous
proteins like serum albumin, sorbitan esters, oleic acid, lecithin,
amino acids such as glycine, buffers, salts, sugars or sugar
alcohols. Aerosols generally are prepared from isotonic
solutions.
Pharmaceutical compositions of this invention suitable for
parenteral administration comprise a subject composition in
combination with one or more pharmaceutically-acceptable sterile
isotonic aqueous or non-aqueous solutions, dispersions, suspensions
or emulsions, or sterile powders which may be reconstituted into
sterile injectable solutions or dispersions just prior to use,
which may contain antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
Examples of suitable aqueous and non-aqueous carriers which may be
employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate and cyclodextrins. Proper fluidity may
be maintained, for example, by the use of coating materials, such
as lecithin, by the maintenance of the required particle size in
the case of dispersions, and by the use of surfactants. The
efficacy of treatment with the subject compositions may be
determined in a number of fashions known to those of skill in the
art.
Throughout the description, where compositions are described as
having, including, or comprising specific components, it is
contemplated that compositions also consist essentially of, or
consist of, the recited components. Similarly, where processes are
described as having, including, or comprising specific process
steps, the processes also consist essentially of, or consist of,
the recited processing steps. Except where indicated otherwise, the
order of steps or order for performing certain actions are
immaterial so long as the invention remains operable. Moreover,
unless otherwise noted, two or more steps or actions may be
conducted simultaneously.
EXAMPLES
The compounds of the present invention can be prepared in a number
of ways well known to one skilled in the art of organic synthesis.
More specifically, compounds of the invention may be prepared using
the reactions and techniques described herein. In the description
of the synthetic methods described below, it is to be understood
that all proposed reaction conditions, including choice of solvent,
reaction atmosphere, reaction temperature, duration of the
experiment and workup procedures, can be chosen to be the
conditions standard for that reaction, unless otherwise indicated.
It is understood by one skilled in the art of organic synthesis
that the functionality present on various portions of the molecule
should be compatible with the reagents and reactions proposed.
Substituents not compatible with the reaction conditions will be
apparent to one skilled in the art, and alternate methods are
therefore indicated. The starting materials for the examples are
either commercially available or are readily prepared by standard
methods from known materials.
Example 1 Preparation of
N-acetyl-(R)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid
(N-Acetyl E2); Compound A
To (R)-(-)-3-(4-aminophenyl)-2-methoxypropionic acid (40 g) in a
0.5 L glass reactor was added ethyl acetate (80 g) and acetic
anhydride (62.8 g). The mixture was stirred at 90.degree. C. for 1
hour. Upon cooling, the solvent was removed by vacuum distillation,
providing an oily residue. To this residue was added water (120 g)
and ethyl acetate (120 g). After stirring for 10 min at 35.degree.
C., the layers were separated and the aqueous layer discarded. The
organic layer solvent was removed by vacuum distillation. Acetone
(120 g) was then added and the resulting mixture was warmed until
dissolution was complete. The solution was cooled to 0.degree. C.,
and the product precipitated which was collected by filtration. The
solid was rinsed with acetone (20 g) and dried at 65.degree. C. to
afford 26 g of the title compound.
Example 2 Docking Studies
The binding of compounds A, B, and their non-acetylated
derivatives, (as well as 5-aminosalicyclic acid (5-ASA) and
5-acetamido-hydroxybenzoic acid) to PPAR.gamma. and PPAR.alpha.
receptors is evaluated.
While 5-ASA shows good affinity for PPAR.gamma., the N-acetylation
of 5-ASA led to a rigid linear structure that did not occupy the
active site in a optimal way. A loss of the hydrogen bond between
H449 and the phenolic group of the compound occurred which may
explain the inactivity of NAc-5-ASA. The binding of compound B and
its non-acetylated counterpart into PPAR.gamma. indicated that
these compounds may activate the receptor based on the receptor's
binding structural prerequisites. Superposition of the compounds
indicated that they bind to different parts of the active site.
The binding of compound A and its non acetylated counterpart
3-(4-aminophenyl)-2-methoxypropanoic acid) into PPAR.gamma.
indicated that these compounds may also activate the receptor. In
contrast to compound B, the superposition of compound A free amine
and N-acetyl derivative show that they occupy the same portion of
the active site, indicating a possible similarity in activity.
Example 3 Anti-Murine Colitis Model
Colitis in C57bI6 mice is induced by administering TNBS (150 mg/kg)
by oral gavage on day -3. Stool samples were taken 8 hours after
administration. At day 0-5, N-acetylated E2 (30 mM) was
administrated by oral gavage. On day 5, mice were analyzed to
obtain a mortality macroscopic score (Wallace, Gastroenterology 96:
29-36, 1989).
As shown in FIG. 1, mortality was comparable between mice given
TNBS versus those given TNBS and N-acetyl E2. However, as shown in
FIG. 2, the level of colonic lesions was significantly less in mice
given TNBS and N-acetyl E2 compared to those given TNBS alone. FIG.
3 demonstrates how MPO (myleoperoxidase) decreased with
administration of N-acetyl E2 with TNBS. In FIG. 4, the Ameho score
(Gut 41: 487-493, 1997) indicated that colonic inflammation had
decreased with administration of N-acetyl E2 with TNBS.
Example 4 Keratinocytes
To assess the possible toxic or cytostatic effect of the substances
under study, a spectrophotometric test (MTT) was carried out. The
human primary keratinocytes, isolated from skin biopsies, were
plated in wells of a 24-well plate in suitable medium with addition
of antibiotics, calcium, and specific growth factors. At around 70%
confluence, the cells were exposed to the presence of Compound A,
at various concentrations (0.1-1-2 mM), for 24 and 48 h in suitable
medium with addition of antibiotics, calcium, but no growth
factors. This culture condition was done for all the subsequent
experiments. At the end of the treatment, the MTT test was done.
The results are indicated in FIG. 5. Compound A in all
concentrations used did not show any effect on cellular
vitality.
Example 5 TNF Alpha
Analysis of the inhibition of compound A of the mRNA induction of
the proinflammatory cytokine TNF-alpha by H.sub.2O.sub.2 was
carried out by Real time RT-PCR. The keratinocytes were plated in
dishes of 6 cm/O. At 80% confluence, the cells were treated with
H.sub.2O.sub.2 (300 .mu.M) in presence of Compound A at the three
concentrations (0.01-0.1-0.5 mM) for 6 h. At the end of the
treatment, the cells were lysed in a lysis buffer and subjected to
isolation and subsequent retrotranscription of the RNA. Compound A
proved able to inhibit the expression of the mRNA of TNF-.alpha.
induced by H.sub.2O.sub.2 at the two higher doses (0.1 mM; 0.5 mM).
The higher dose demonstrated a complete inhibition of the
proinflammatory cytokine with an effect similar to troglitazone
(Tg). (FIG. 6)
Example 6 Inhibition of mRNA Expression of IL-6 Induced by Presence
of IFN-.gamma.
Analysis of the inhibition by compound A of the mRNA induction of
the proinflammatory cytokine IL-6 by IFN-.gamma. was done through
Real time RT-PCR. The keratinocytes were plated in dishes of 6
cm/O.
At 80% confluence, the cells were treated with IFN-.gamma. (30
ng/ml) in presence of compound A (N-Acetylged) at the three
concentrations (0.01-0.1-0.5 mM) for 6 h. At the end of the
treatment, the cells were lysed in a lysis buffer and subjected to
isolation and subsequent retrotranscription of the RNA The results
(as shown in FIG. 7) reveal the ability of Compound A to inhibit
the expression of the inflammatory cytokine induced by presence of
IFN-.gamma. which does not appear to be dose-dependent.
Example 7 Inhibitory Capacity on the Activation of Nuclear Factor
NF-kB Induced by Presence of H.sub.2O.sub.2
Evaluation of the inhibition by compound A of the activation of
nuclear transcription factor NF-kB induced by the presence of
H.sub.2O.sub.2 was done by analysis in cytofluorimetry.
The keratinocytes were plated in wells of a 12-well plate. At 80%
confluence, the cells were treated with H.sub.2O.sub.2 (300 .mu.M)
in presence of compound A at the three concentrations (0.01-0.1-0.5
mM) for 1 h. At the end of the treatment, the cells were fixed in
paraformaldehyde, permeabilized in methanol and then incubated in
presence of the specific antibody of subunit p65. Compound A
revealed an inhibitory effect on the activation and subsequent
translocation of NF-kB in dose-dependent manner (FIG. 8).
Example 8 Inhibition of Protein Expression of IL-6 Induced by
Presence of LPS
Analysis of the inhibition by Compound A of the protein induction
of IL-6 by LPS (lipopolysaccharide) was done with the ELISA kit.
The keratinocytes were plated in wells of a 24-well plate. At 80%
confluence, the cells were treated with LPS (10 .mu.g/ml) in
presence of compound A at the three concentrations (0.01-0.1-0.5
mM) for 24 h. At the end of the treatment, the supernatant was
decanted, centrifuged so as to remove any cell detritus, and kept
at -80.degree. C. until the time of the analysis. The quantity of
IL-6 present in the supernatant was normalized by the protein
concentration of the sample itself. The results (FIG. 9) revealed
the ability of compound A to inhibit, in dose-dependent manner, the
protein expression of the inflammatory cytokine under study.
Example 9--Human Sebocytes
To assess the possible toxic or cytostatic effect of the substances
under study, a spectrophotometric test (MTT) was carried out. The
sebocytes were plated in wells of a 24-well plate in suitable
medium with addition of antibiotics, calcium and EGF. At roughly
70% confluence, the cells were exposed to the presence of compound
A, in various concentrations (0.1-0.5-1-2 mM), for 24 and 48 h. At
the end of the treatment, the MTT test was performed. Compound A in
all concentrations used demonstrated no effects on cell vitality.
(FIG. 10)
Example 10 Evaluation of the Inhibitory Capacity of a Compound on
Sebogenesis Induced by Stimuli of Lipid Type (Linoleic Acid,
Testosterone)
Analysis of the inhibition by (compound A) of sebogenesis induced
by treatment with linoleic acid (LA) and with testosterone (TST)
was evaluated by spectrofluorimetry, using Nile Red as selective
marker of intracellular lipids (Nile Red Assay). The sebocytes were
plated in wells of a 24-well plate. Next day, they were deprived of
serum (2%) and after 24 h they were stimulated, for another 24 h,
with LA (10-4M), TST (20 nM) in presence or in absence of A (1 mM).
At the end of the treatment, the sebocytes were stained with Nile
Red. The quantitative analysis was done by spectrofluorimetry,
which made it possible to distinguish between neutral lipids and
polar lipids based on the different wavelength of excitation and
emission. The data obtained revealed that the treatment with LA is
able to induce lipid synthesis and that the combined LA+TST
treatment further increases this effect. The presence of Compound A
proved able to reduce the lipidogenic stimulus. (FIG. 11).
Example 11 Evaluation of the Inhibitory Capacity on Sebogenesis
Induced by Stimuli of Lipid Type (Linoleic Acid, Testosterone):
Evaluation of Fatty Acids and Squalene
In order to evaluate in greater detail the inhibition by Compound A
of sebogenesis induced by LA and TST, assays were performed on the
lipid extract of the sebocytes using gas chromatography coupled
with mass spectrometry (GC-MS). The sebocytes were treated by the
scheme described for the Nile Red assay. At the end of the
treatment, the cells were removed and then the lipid extraction was
done by using organic solvents. One part of the extract was used to
analyze the fatty acid composition, while the other part was used
for the determination of the quantity of squalene, a lipid
characteristic of sebum. The fatty acid assay showed that the
lipidogenic stimulus induced by the treatment with LA and LA+TST
was reduced by the presence of A (FIG. 12A). These results are
confirmed by the squalene analysis. (FIG. 12B)
Example 12 Evaluation of the Inhibitory Capacity on Sebogenesis
Induced by Stimuli of Lipid Type (Linoleic Acid, Testosterone)
Analysis of the inhibition by compound A of sebogenesis induced by
treatment with linoleic acid (LA) and with testosterone (TST) was
evaluated by spectrofluorimetry, using Nile Red as selective marker
of intracellular lipids (Nile Red Assay). The sebocytes were plated
in wells of a 24-well plate. Next day, they were deprived of serum
(2%) and after 24 h they were stimulated, for another 24 h, with LA
(10-4M), TST (20 nM) in presence or in absence of compound A (1
mM). At the end of the treatment, the sebocytes were stained with
Nile Red. The quantitative analysis was done by spectrofluorimetry,
which made it possible to distinguish between neutral lipids and
polar lipids based on the different wavelength of excitation and
emission. The data obtained (FIG. 13) revealed that the treatment
with LA is able to induce lipid synthesis and that the combined
LA+TST treatment further increases this effect. The presence of A
proved able to reduce the lipidogenic stimulus. No differences were
observed in regard to the times of treatment with the A.
REFERENCES
All publications and patents mentioned herein, including those
items listed below, are hereby incorporated by reference in their
entirety as if each individual publication or patent was
specifically and individually incorporated by reference. In case of
conflict, the present application, including any definitions
herein, will control.
EQUIVALENTS
While specific embodiments of the subject invention have been
discussed, the above specification is illustrative and not
restrictive. Many variations of the invention will become apparent
to those skilled in the art upon review of this specification. The
full scope of the invention should be determined by reference to
the claims, along with their full scope of equivalents, and the
specification, along with such variations.
Unless otherwise indicated, all numbers expressing quantities of
ingredients, reaction conditions, and so forth used in the
specification and claims are to be understood as being modified in
all instances by the term "about." Accordingly, unless indicated to
the contrary, the numerical parameters set forth in this
specification and attached claims are approximations that may vary
depending upon the desired properties sought to be obtained by the
present invention.
* * * * *
References